To the Editor:The article by Marongiu and colleagues in the recent issue of the Journal unravels several interesting effects of 5% CO2 on lung pathophysiology in a porcine model of unilateral pulmonary artery (PA) ligation (1). Pathological changes in the lung due to unilateral PA ligation and the effects of 5% CO2 are noticeable. Nevertheless, the corresponding physiological changes do not reflect the extent of injury due to left PA ligation. Despite a substantial increase in wasted or dead space ventilation due to left PA ligation, the PaCO–end-tidal CO2 (ETCO) gradient remained constant. Surprisingly, PaCO did not rise significantly in the isolated PA ligation group at all time points from 2 hours to 48 hours despite worsening lung pathology, declining lung compliance, and constant ventilator settings. Moreover, PaCO decreased from 39 mm Hg at baseline to 33 mm Hg at 48 hours in the isolated PA ligation group. Notably, in the 5% CO2 group, PaCO rose significantly to 67 mm Hg at 2 hours after ligation from the baseline value of 36 mm Hg. Additionally, the magnitude of increase in ETCO was similar to PaCO, and the PaCO–ETCO gradient became negative. Intuitively, CO2 rebreathing cannot be solely responsible for a substantial increase in PaCO in the 5% CO2 group.Main branch PA closure during Blalock-Taussig shunt and cavopulmonary anastomosis has been associated with a significant rise in PaCO and PaCO–ETCO gradient (2). In cyanotic congenital heart disease, oxygenation and CO2 elimination are critically dependent on pulmonary blood flow, and the rise in PaCO and PaCO–ETCO gradient during transient PA branch occlusion is obvious (3). The PaCO–ETCO gradient has also been noted to increase in patients with acute pulmonary thromboembolism, pulmonary artery banding, or single-lung ventilation despite normal or excessive preoperative pulmonary blood flow (4). Therefore, readers may be curious to hear from the authors why PaCO did not rise after PA ligation in isolated ligation groups and the 5% CO2 inhalation group whether PaCO increased due to rebreathing or PA ligation.The authors asserted that lung injury is a major determinant of PA pressure that does not correspond to hourly hemodynamic data. Pulmonary vascular resistance (PVR) in the 5% CO2 group nearly doubled at the 12th hour from the baseline (360 dyne/s/cm−5 versus 189 dyne/s/cm−5). A higher trend in PVR was maintained through 48 hours compared with the ligation group alone. However, the rise in mean arterial pressure after double insults of hypercarbia and PA ligation appears clinically insignificant. This finding is indeed clinically promising for anesthesiologists and critical care physicians managing various cardiac surgeries, noncardiac surgeries, and acute respiratory distress syndrome. Considering the extent of the rise in PA pressure after ligation and hypercarbia in the 5% CO2 group in this study, a ventilator strategy involving permissive hypercapnia and hypercarbia to avoid volutrauma in acute respiratory distress syndrome appears safe. Furthermore, 5% CO2 may offer protection from lung damage during PA ligation (pneumonectomy or lobectomy), PA banding, and PA occlusion to facilitate Blalock-Taussig shunt and cavopulmonary anastomosis.PA ligation is akin to acute thromboembolism, which may lead to a rapid rise in right ventricular load, right ventricular dilatation, and reduction in cardiac output (5). Interestingly, cardiac output rose (4.4 L/min to 5.1 L/min) in the 5% CO2 group, and therefore ligation and hypercarbia did not seem to produce right ventricular dysfunction until the end of the study. Thus, assessing change in systolic or diastolic right ventricular function compared with baseline after pulmonary artery ligation or hypercarbia could have further provided mechanistic insight.Finally, the authors have stressed that the diversion of minute ventilation instead of blood flow is responsible for pulmonary edema in the nonligated lung (right lung). Nevertheless, hypercarbia in the 5% CO2 group produced pulmonary vasoconstriction (PVR = 360 and 352 dyne/s/cm−5 at 12 and 24 hours) during the initial phases, which could have prevented the development of pulmonary edema in the right lung. Moreover, in addition to excessive ventilation in producing lung injury, the role of toxic or inflammatory mediators from the ligated hypoxic, anoxic, or infarcted lung in inflicting lung damage to the nonligated lung needs to be investigated.